We endeavor to further the state of the art using nanomaterials in the field of pharmaceutical dosage forms and formulation technology.
Nanotechnology is a field of applied science and technology covering a broad range of topics. The main unifying theme is the control of matter on a scale smaller than one micrometer as well as the fabrication of devices on this same length scale. Worldwide research is currently being conducted in countless areas to discover new and useful areas where nanotechnology can be exploited commercially. The research involves potential utility in industrial applications, such as pharmaceutical packaging as well as other areas of medicine and bio-energy just to name a few.
Despite the apparent simplicity of this definition, nanotechnology actually encompasses diverse lines of inquiry. Nanotechnology cuts across many disciplines, including colloidal science, chemistry, applied physics, biology. It could variously be seen as an extension of existing sciences into the nanoscale, or as a recasting of existing sciences using a newer, more modern term.
Two main approaches are used in nanotechnology. One is a “bottom-up” approach where materials and devices are built from molecular components which assemble themselves chemically using principles of molecular recognition. The other being a “top-down” approach where nano-objects are constructed from larger entities without atomic-level control.
Nanomaterials are materials having unique properties arising from their nanoscale dimensions. The use of nanoscale materials can also be used for bulk applications. In fact, most present commercial applications of nanotechnology are of this flavor.
Nanomaterials from a “top-down” design have certain scaling deficiencies which must be assessed. For example, A number of physical phenomena become noticeably pronounced as the size of the system decreases. These include statistical mechanical effects, as well as quantum mechanical effects, for example the “quantum size effect” where the electronic properties of solids are altered with great reductions in particle size. This effect does not come into play by going from macro to micro dimensions. However, it becomes dominant when the nanometer size range is reached. Additionally, a number of physical properties change when compared to macroscopic systems. One example is the increase in surface area to volume of materials. This catalytic activity also opens potential risks in their interaction with biomaterials.
Additionally, materials reduced to the nanoscale can suddenly show very different properties compared to what they exhibit on a macroscale, enabling unique applications. For instance, opaque substances become transparent (copper); inert materials become catalysts (platinum); stable materials turn combustible (aluminum); solids turn into liquids at room temperature (gold); insulators become conductors (silicon) to name a few.
Additionally, nanosize powder particles are important for the achievement of uniform nanoporosity and similar applications. However, the tendency of small particles to form clumps (“agglomerates”) is a serious technological problem that impedes such applications.
Another deficiency is that the volume of an object decreases as the third power of its linear dimensions, but the surface area only decreases as its second power. This somewhat subtle and unavoidable principle has huge ramifications. For example the power of a drill (or any other machine) is proportional to the volume, while the friction of the drill's bearings and gears is proportional to their surface area. For a normal-sized drill, the power of the device is enough to handily overcome any traction. However, scaling its length down by a factor of 1000, for example, decreases its power by 10003 (a factor of a billion) while reducing the friction by only 10002 (a factor of “only” a million). Proportionally it has 1000 times less power per unit friction than the original drill. If the original friction-to-power ratio was, say, 1%, that implies the smaller drill will have 10 times as much friction as power. The drill is useless.
This is why, while super-miniature electronic integrated circuits can be made to function, the same technology cannot be used to make functional mechanical devices in miniature.
Nanomaterials from a “bottom-up” design also have certain deficiencies which must be assessed. Modern synthetic chemistry has reached the point where it is possible to prepare small molecules to almost any structure. These methods are used today to produce a wide variety of useful chemicals such as pharmaceuticals or commercial polymers. However, the ability of this to extend into supramolecular assemblies consisting of many molecules arranged in a well defined manner is problematic. Such bottom-up approaches should, broadly speaking, be able to produce devices in parallel and much cheaper than top-down methods. However, most useful structures require complex and thermodynamically unlikely arrangements of atoms. The basic laws of probability and entropy make it very unlikely that atoms will “self-assemble” in useful configurations, or can be easily and economically nudged to do so. About the only example of this is a crystal growing, for which Nanotechnology cannot take any credit.
Given the deficiencies associated with “top-down” and “bottom-up” nanomaterials, it becomes clear that providing a functional approach to nanotechnology (i.e. the development of nanomaterials of a desired functionality) can be problematic.
Finally, implementing nanotechnologies in highly-regulated bulk packaging applications, such as pharmaceutical formulation and dosage forms, only compounds problems. The present invention overcomes these problems.
In relation to pharmaceutical dosage forms, soft gelatin capsules, now more commonly known as softgels, have been well known and widely used for many years. Softgels generally comprise an outer shell primarily made of gelatin, a plasticizer, and water, and a fill contained within the shell. However, other materials as a substitute for gelatin can be used, such as gum acacia and other non-gelatin substitutes. The fill may be selected from any of a wide variety of substances that are compatible with the shell. Softgels are widely used in the pharmaceutical industry as an oral dosage form containing many different types of pharmaceutical and vitamin products. In addition to use as an oral dosage form for drugs and vitamins, soft gelatin capsules or softgels are also designed for use as suppositories for rectal or vaginal use. Other uses are for topical and ophthalmic preparations and the like. The cosmetic industry also uses softgels as a specialized package for various types of perfumes, oils, shampoos, skin creams and the like. Softgels are available in a great variety of sizes and shapes, including round shapes, oval shapes, oblong shapes, tube shapes and other special types of shapes such as stars. The finished capsules or softgels can be made in a variety of colors. In addition, opacifiers may be added to the shell.
Although softgels can be made in a wide variety of shapes, sizes and colors, because of the wide range of use of softgels, there is a definite need to provide improved means of monitoring quality of the dosage form (i.e. capsule) and other means of identification. In this regard, it is quite common today to have an indicia of some type printed on each softgel after formation. The printing material may be any suitable dye or pigment. In some equipment, this has the disadvantage of requiring the use of an additional machine that will align the softgels and hold them in a desired oriented position for the application of the dye or ink. The use of additional equipment and procedural steps adds to the overall cost of manufacture of the softgels and, therefore, this system is considered disadvantageous. Also, the printing of each softgel can be done over only a limited portion of the exterior surface of the softgel and may not be readily read or even seen by the consumer. Specific examples of known processes and machines used for applying some type of identification on the softgels are those shown, for example, in Power (Posner) U.S. Pat. No. 2,449,139; Scherer U.S. Pat. No. 2,623,494; Scherer U.S. Pat. No. 2,688,775; Scherer U.S. Pat. No. 2,688,775; Taylor U.S. Pat. No. 3,124,840; Hansen U.S. Pat. No. 3,203,347; and Vincent U.S. Pat. No. 3,333,031.
In the rotary die process for manufacturing softgels, two gelatin ribbons are prepared, fed simultaneously to the fill area, and simultaneously and continuously filled, formed, hermetically sealed, and automatically cut between two rotary dies. The Scherer U.S. Pat. No. 2,623,494 relates to a banding machine for softgels. In this machine, the identifying band is applied to each individual capsule after the capsule is formed. The Scherer U.S. Pat. No. 2,688,775 shows a method for applying a brand to the exterior surface of a gelatin capsule. The Scherer U.S. Pat. No. 2,703,047 discloses a similar system of branding the filled capsules. In the Taylor U.S. Pat. No. 3,124,840, a printing element is provided in order to print on the gelatin strip prior to the formation of the capsule. The Hansen U.S. Pat. No. 3,203,347 shows a marking fluid that is printed on the gelatin ribbon used to make the softgels. The Vincent U.S. Pat. No. 3,333,031 shows dying of the gelatin strip before capsule formation. Even though efforts have been made to manufacture gelatin capsule and distinguish them from those of others by using different shapes, sizes, colors, color combinations, branding, banding, and printing, there still is a need to provide a way to even more uniquely identify whether the drug product within the dosage form is still viable while accomplishing this in a very unique, economical, and simplified manner.
In addition, growing demand for patient-friendly drug delivery forms has also increased interest in aseptic prefilled systems, such as pre-filled syringes. Pre-filled dosage forms reduce the risk of misidentification, dosage error and contamination. Additionally, pre-filled dosage forms eliminate container overfill that can be associated with vials. This is important when the product is in short supply, such as a vaccine. However, switching to a prefilled syringe presents its own set of challenges for manufacturers. In a prefilled syringe, a drug is exposed to materials it does not encounter in a vial. For example, lubrication is of limited importance in a stopper for a vial. In syringes, however, lubricity is essential to proper functioning of the device. The plunger must move smoothly and easily. Silicone is often used to ensure lubricity. Determining how silicone will interact with a given drug's stability and aggregation is a problem for both formulators and fillers. The current invention addresses these problems.
Finally, the need for quality monitoring in supply chain management of dosage forms is becoming increasingly important. Cold Chain refers to a subset of the total supply chain involving the production, storage, and distribution of drug products that require some level of temperature control in order to retain the drugs key characteristics and properties. The most critical portion of cold chain management is the distribution phase of drugs to the end-user (i.e. patient). The Food and Drug Administration requires that these drug products be stored under appropriate conditions so that their identity, strength, quality, effectiveness, and purity are not affected. However, many variables affect these properties, such as facility temperature deviation, airflow, air quality, duration of storage, container integrity, and seasonal considerations. Currently, quality is monitored on a destination-by-destination method.
The aforementioned background shows that a fundamental change is needed in the way quality is monitored for pharmaceutical formulations and dosage forms from the point of packaging until the time the drug reaches the end user. The present invention addresses these problems.